Misoprostol is extensively
absorbed, and undergoes rapid deÂesterification to its free acid, which is
responsible for its clinical activity and, unlike the parent compound, is
detectable in plasma. The alpha side chain undergoes beta oxidation and the
beta side chain undergoes omega oxidation followed by reduction of the ketone
to give prostaglandin F analogs.
In normal volunteers, Cytotec
(misoprostol) is rapidly absorbed after oral administration with a Tmax of
misoprostol acid of 12 ± 3 minutes and a terminal half-life of 20–40 minutes.
There is high variability of
plasma levels of misoprostol acid between and within studies but mean values
after single doses show a linear relationship with dose over the range of
200–400 mcg. No accumulation of misoprostol acid was noted in multiple dose
studies; plasma steady state was achieved within two days.
Maximum plasma concentrations
of misoprostol acid are diminished when the dose is taken with food and total
availability of misoprostol acid is reduced by use of concomitant antacid.
Clinical trials were conducted with concomitant antacid, however, so this
effect does not appear to be clinically important.
|Mean ± SD
||417 ± 135
||14 ± 8
||689 ± 315
||349 ± 108*
||20 ± 14
|With High Fat Breakfast
||303 ± 176*
||64 ± 79*
|* Comparisons with fasting results statistically significant,
After oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine.
Pharmacokinetic studies in patients with varying degrees of renal impairment
showed an approximate doubling of T½, Cmax, and AUC compared to normals, but
no clear correlation between the degree of impairment and AUC. In subjects over
64 years of age, the AUC for misoprostol acid is increased. No routine dosage
adjustment is recommended in older patients or patients with renal impairment,
but dosage may need to be reduced if the usual dose is not tolerated.
Drug interaction studies
between misoprostol and several nonsteroidal anti-inflammatory drugs showed no
effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin
AUC, not thought to be clinically significant.
Pharmacokinetic studies also
showed a lack of drug interaction with antipyrine and propranolol when these
drugs were given with misoprostol. Misoprostol given for 1 week had no effect
on the steady state pharmacokinetics of diazepam when the two drugs were
administered 2 hours apart.
The serum protein binding of
misoprostol acid is less than 90% and is concentration-independent in the
After a single oral dose of
misoprostol to nursing mothers, misoprostol acid was excreted in breast milk.
The maximum concentration of misoprostol acid in expressed breast milk was
achieved within 1 hour after dosing and was 7.6 pg/ml (CV 37%) and 20.9 pg/ml
(CV 62%) after single 200 μg and 600
μg misoprostol administration, respectively. The misoprostol acid
concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose.
Misoprostol has both
antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal
protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency
of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate
and mucus secretion and may contribute to the mucosal damage caused by these
agents. Misoprostol can increase bicarbonate and mucus production, but in man
this has been shown at doses 200 mcg and above that are also antisecretory. It
is therefore not possible to tell whether the ability of misoprostol to reduce
the risk of gastric ulcer is the result of its antisecretory effect, its
mucosal protective effect, or both.
In vitro studies on canine parietal cells using tritiated
misoprostol acid as the ligand have led to the identification and
characterization of specific prostaglandin receptors. Receptor binding is
saturable, reversible, and stereospecific. The sites have a high affinity for
misoprostol, for its acid metabolite, and for other E type prostaglandins, but
not for F or I prostaglandins and other unrelated compounds, such as histamine
or cimetidine. Receptor-site affinity for misoprostol correlates well with an
indirect index of antisecretory activity. It is likely that these specific
receptors allow misoprostol taken with food to be effective topically, despite
the lower serum concentrations attained.
Misoprostol produces a moderate decrease in pepsin
concentration during basal conditions, but not during histamine stimulation. It
has no significant effect on fasting or postprandial gastrin nor on intrinsic
Effects On Gastric Acid Secretion
Misoprostol, over the range of 50–200 mcg, inhibits basal
and nocturnal gastric acid secretion, and acid secretion in response to a
variety of stimuli, including meals, histamine, pentagastrin, and coffee.
Activity is apparent 30 minutes after oral administration and persists for at
least 3 hours. In general, the effects of 50 mcg were modest and shorter lived,
and only the 200-mcg dose had substantial effects on nocturnal secretion or on
histamine and meal-stimulated secretion.
Cytotec has been shown to produce uterine contractions
that may endanger pregnancy. (See BOXED WARNINGS.)
Other Pharmacologic Effects
Cytotec does not produce clinically significant effects
on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone,
growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin,
gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric
acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary
function, or the cardiovascular system are not modified by recommended doses of
In a series of small short-term (about 1 week)
placebo-controlled studies in healthy human volunteers, doses of misoprostol
were evaluated for their ability to reduce the risk of NSAID-induced mucosal
injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen,
and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate
of significant endoscopic injury from about 70–75% on placebo to 10–30% on
misoprostol. Doses of 25–200 mcg q.i.d. reduced aspirin-induced mucosal injury
Reducing The Risk Of Gastric Ulcers Caused By
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Two 12-week, randomized, double-blind trials in
osteoarthritic patients who had gastrointestinal symptoms but no ulcer on
endoscopy while taking an NSAID compared the ability of 200 mcg of Cytotec, 100
mcg of Cytotec, and placebo to reduce the risk of gastric ulcer (GU) formation.
Patients were approximately equally divided between ibuprofen, piroxicam, and
naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg
dose caused a marked, statistically significant
reduction in gastric ulcers in both studies. The lower dose was somewhat less
effective, with a significant result in only one of the studies.
Reduction of Risk of Gastric
Ulcers Induced by Ibuprofen, Piroxicam, or Naproxen [No. of patients with ulcer(s) (%)]
|Study No. 1
| Cytotec 200 mcg q.i.d. (n=74)
| Cytotec 100 mcg q.i.d. (n=77)
|Study No. 2
|Cytotec 200 mcg q.i.d. (n=65)
| Cytotec 100 mcg q.i.d. (n=66)
|Studies No. 1 & No. 2**
| Cytotec 200 mcg q.i.d. (n=139)
| Cytotec 100 mcg q.i.d. (n=143)
|* Statistically significantly different from placebo at
the 5% level.
** Combined data from Study No. 1 and Study No. 2.
In these trials there were no significant differences
between Cytotec and placebo in relief of day or night abdominal pain. No effect
of Cytotec in reducing the risk of duodenal ulcers was demonstrated, but
relatively few duodenal lesions were seen.
In another clinical trial, 239 patients receiving aspirin
650–1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of
duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg
q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study
evaluated the possible interference of Cytotec on the efficacy of aspirin in
these patients with rheumatoid arthritis by analyzing joint tenderness, joint
swelling, physician's clinical assessment, patient's assessment, change in ARA
classification, change in handgrip strength, change in duration of morning
stiffness, patient's assessment of pain at rest, movement, interference with
daily activity, and ESR. Cytotec did not interfere with the efficacy of aspirin
in these patients with rheumatoid arthritis.
A reversible increase in the number of normal surface
gastric epithelial cells occurred in the dog, rat, and mouse. No such increase
has been observed in humans administered Cytotec for up to 1 year.
An apparent response of the female mouse to Cytotec in
long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly
of the medulla of sternebrae. Hyperostosis did not occur in long-term studies
in the dog and rat and has not been seen in humans treated with Cytotec.